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| United States Patent |
6,194,405
|
|
Gil-Lopetegui
, et al.
|
February 27, 2001
|
Method of using substituted tetracyclic tetrahydrofuran derivatives
Abstract
This invention concerns the compounds of formula (I),
##STR1##
the N-oxide forms, the pharmaceutically acceptable addition salts and the
stereoisomeric forms thereof, wherein n is zero to 6; p and q are zero to
4; r is zero to 5; R.sup.1 and R.sup.2 each independently are hydrogen;
optionally substituted C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl;
halomethylcarbonyl; or R.sup.1 and R.sup.2 taken together with the
nitrogen atom to which they are attached may form a morpholinyl ring or an
optionally substituted heterocycle; each R.sup.3 and R.sup.4 independently
are halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino,
mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkylcarbonylamino,
aminosulfonyl, mono- or di(C.sub.1-6 alkyl)aminosulfonyl, C.sub.1-6 alkyl,
C.sub.1-6 alkyloxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkyloxycarbonyl;
each R.sup.5 independently is C.sub.1-6 alkyl, cyano or halomethyl; X is
CR.sup.6 R.sup.7, NR.sup.8, O, S, S(.dbd.O) or S(.dbd.O).sub.2 ; aryl is
optionally substituted phenyl; provided that the compound is other than
(.+-.)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:
6,7]-cyclohepta[1,2-b]-furan-2-methanamine oxalic acid. The compounds of
formula (I) may be used as therapeutic agents in the treatment or the
prevention of CNS disorders, cardiovascular disorders or gastrointestinal
disorders.
| Inventors:
|
Gil-Lopetegui; Pilar (Toledo, ES);
Fernandez-Gadea; Francisco Javier (Toledo, ES);
Meert; Theo Frans (Boom, BE)
|
| Assignee:
|
Janssen Pharmaceutica N.V. (BE)
|
| Appl. No.:
|
533625 |
| Filed:
|
March 22, 2000 |
Foreign Application Priority Data
| Current U.S. Class: |
514/215; 514/231.5; 514/232.8; 514/236.8; 514/237.2; 514/254.11; 514/321; 514/323; 514/324; 514/414; 514/415; 514/417; 514/422; 514/425; 514/431; 514/450; 514/452; 514/453; 514/459; 514/461 |
| Intern'l Class: |
A01N 043/46; 450; 452; 453; 459; 461 |
| Field of Search: |
514/215,231.5,232.8,236.8,237.2,253,254,321,323,324,414,415,417,422,425,431
|
References Cited
U.S. Patent Documents
| 5089507 | Feb., 1992 | Vecchietti et al. | 514/336.
|
| 5286735 | Feb., 1994 | Bonnaud et al. | 514/321.
|
| 5310743 | May., 1994 | Schilling et al. | 514/311.
|
| 5541195 | Jul., 1996 | Schilling et al. | 514/311.
|
| 5646144 | Jul., 1997 | Schilling et al. | 514/241.
|
| Foreign Patent Documents |
| 0 532 398 | Mar., 1993 | EP.
| |
| WO 97/10212 | Mar., 1997 | WO.
| |
Primary Examiner: Kight; John
Assistant Examiner: Covington; Raymond
Attorney, Agent or Firm: Appollina; Mary
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of application Ser. No. 09/155,840,
filed Oct. 6, 1998 U.S. Pat. No. 6,057,441, which was a National Stage
application under 35 U.S.C. .sctn. 371 of PCT/EP97/01829, filed Apr. 9,
1997, which claims priority from EP 96.200.990.8, filed Apr. 12, 1996.
Claims
What is claimed is:
1. A method of treating a central nervous system disorder in a warm-blooded
animal in need thereof comprising administering to the warm-blooded animal
a therapeutically effective amount of a compound of formula (I)
##STR15##
a N-oxide form, a pharmaceutically acceptable addition salt or a
stereochemically isomeric form thereof, wherein:
n is zero, 1, 2, 3, 4, 5, or 6;
p is zero, 1, 2, 3 or 4;
q is zero, 1, 2, 3 or 4;
r is zero, 1, 2, 3, 4 or 5;
R.sup.1 and R.sup.2 each independently are hydrogen; C.sub.1-6 alkyl;
C.sub.1-6 alkylcarbonyl; halomethylcarbonyl; C.sub.1-6 alkyl substituted
with hydroxy, C.sub.1-6 alkyloxy, carboxyl, C.sub.1-6 alkylcarbonyloxy,
C.sub.1-6 alkyloxycarbonyl or aryl; or R.sup.1 and R.sup.2 taken together
with the nitrogen atom to which they are attached may form a morpholinyl
ring or a radical of formula:
##STR16##
wherein: R.sup.9, R.sup.10, R.sup.11 and R.sup.12 each independently are
hydrogen, halo, halomethyl, or C.sub.1-6 alkyl;
m is zero, 1, 2, or 3;
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 each independently are hydrogen,
C.sub.1-6 alkyl, aryl or arylcarbonyl; or
R.sup.15 and R.sup.16 taken together may form a bivalent radical C.sub.4-5
alkanediyl;
R.sup.17 is hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl;
halomethylcarbonyl; C.sub.1-6 alkyloxycarbonyl; aryl; di(aryl)methyl;
C.sub.1-6 alkyl substituted with hydroxy, C.sub.1-6 alkyloxy, carboxyl,
C.sub.1-6 alkylcarbonyloxy, C.sub.1-6 alkyloxycarbonyl or aryl;
each R.sup.3 independently is halo, cyano, hydroxy, halomethyl,
halomethoxy, carboxyl, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino,
C.sub.1-6 alkylcarbonylamino, aminosulfonyl, mono- or di(C.sub.1-6
alkyl)aminosulfonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkyloxycarbonyl;
each R.sup.4 independently is halo, cyano, hydroxy, halomethyl,
halomethoxy, carboxyl, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino,
C.sub.1-6 alkylcarbonylamino, aminosulfonyl, mono- or di(C.sub.1-6
alkyl)aminosulfonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkyloxycarbonyl;
each R.sup.5 independently is C.sub.1-6 alkyl, cyano or halomethyl;
X is CR.sup.6 R.sup.7, NR.sup.8, O, S, S(.dbd.O) or S(.dbd.O).sub.2 ;
wherein
R.sup.6 and R.sup.7 each independently are hydrogen, hydroxy, C.sub.1-6
alkyl, halomethyl, C.sub.1-6 alkyloxy or R.sup.6 and R.sup.7 taken
together may form methylene; mono- or di(cyano)methylene;
a bivalent radical of formula --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --,
--(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --O--(CH.sub.2).sub.2 --O--,
--O--(CH.sub.2).sub.3 --O--; or, together with the carbon atom to which
they are attached, a carbonyl;
R.sup.8 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl,
arylcarbonyl, arylC.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylsulfonyl,
arylsulfonyl or arylC.sub.1-6 alkylsulfonyl;
aryl is phenyl; or phenyl substituted with 1, 2 or 3 substituents selected
from halo, hydroxy, C.sub.1-6 alkyl and halomethyl;
provided that the compound is other than
(.+-.)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:
6,7]-cyclohepta[1,2-b]furan-2-methanamine oxalic acid.
2. The method of claim 1 wherein the compound is other than
3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:
6,7]-cyclohepta[1,2-b]furan-2-methanamine.
3. The method of claim 2 wherein R.sup.13, R.sup.14, R.sup.15 and R.sup.16
each independently are hydrogen or C.sub.1-6 alkyl.
4. The method of claim 3 wherein X is CR.sup.6 R.sup.7 or O.
5. The method of claim 5 wherein R.sup.1 and R.sup.2 both are C.sub.1-6
alkyl or R.sup.1 and R.sup.2 are taken together with the nitrogen atom to
which they are attached and form a morpholinyl ring; a radical of formula
(c) or a radical of formula (e).
6. The method of claim 5 wherein the substituents on carbon atoms 3a and
12b have the trans configuration.
7. The method of claim 6 wherein r, p and q are zero.
8. The method of claim 6 wherein p is 1 and R.sup.3 is halo, C.sub.1-6
alkyl or C.sub.1-6 alkyloxy.
9. The method of claim 6 wherein q is 1 and R.sup.4 is halo, C.sub.1-6
alkyl or C.sub.1-6 alkyloxy.
10. The method of claim 1 wherein the compound is
3,3a,8,12b-tetrahydro-N,N-dimethyl-2H-dibenzo[3,4:
6,7]cyclohepta[1,2-b]furan-2-methanamine; a stereochemically isomeric form
or a pharmaceutically acceptable addition salt thereof, or an N-oxide form
thereof.
11. The method of claim 1 wherein the disorder is selected from the group
consisting of anxiety, depression, mild depression, bipolar disorder,
sleep-disorder, sexual disorder, psychosis, borderline psychosis,
schizophrenia, migraine, personality disorder, obsessive-compulsive
disorder, social phobia, panic attack, organic mental disorder, mental
disorder in children, aggression, memory disorder, attitude disorder in
older people, addiction, obesity, bulimia, and addictive properties of
drugs of abuse.
12. The method of claim 1 wherein the disorder is selected from the group
consisting of anxiety, psychosis, depression, migraine and addictive
properties of drugs of abuse.
Description
This invention concerns substituted tetracyclic tetrahydrofuran derivatives
having antipsychotic, cardiovascular and gastrokinetic activity and their
preparations; it further relates to compositions comprising them, as well
as their use as a medicine.
An article by Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407)
describes the synthesis of
(.+-.)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:
6,7]-cyclohepta-[1,2-b]furan-2-methanamine oxalic acid. Said compound was
synthesized as potential antidepressant; however, it was found that this
particular tetrahydrofurfurylamine derivative was inactive as
antidepressant at a dose of 300 mg/kg.
Compounds of similar structure are disclosed in U.S. Pat. No. 4,145,434,
published on Mar. 20, 1979, and involve dibenzo(cyclohepta-, oxepino-,
thiepino-) pyrrolidine derivatives as well as dibenzopyrrolidino azepine
derivatives, having CNS-depressant, antihistamine and antiserotonin
activities. The present compounds differ therefrom structurally by the
presence of a tetrahydrofuran ring instead of a pyrrolidine ring, and are
further distinguished by valuable pharmacological properties, in
particular, they suppress mCPP (metachlorophenylpiperazine) induced
effects in rats.
This invention concerns compounds of formula (I)
##STR2##
the N-oxide forms, the pharmaceutically acceptable addition salts and the
stereochemically isomeric forms thereof, wherein:
n is zero, 1, 2, 3, 4, 5, or 6;
p is zero, 1, 2, 3 or 4;
q is zero, 1, 2, 3 or 4;
r is zero, 1, 2, 3, 4 or 5;
R.sup.1 and R.sup.2 each independently are hydrogen; C.sub.1-6 alkyl;
C.sub.1-6 alkylcarbonyl; halomethylcarbonyl; C.sub.1-6 alkyl substituted
with hydroxy, C.sub.1-6 alkyloxy, carboxyl, C.sub.1-6 alkylcarbonyloxy,
C.sub.1-6 alkyloxycarbonyl or aryl; or R.sup.1 and R.sup.2 taken together
with the nitrogen atom to which they are attached may form a morpholinyl
ring or a radical of formula:
##STR3##
wherein:
R.sup.9, R.sup.10, R.sup.11 and R.sup.12 each independently are hydrogen,
halo, halomethyl, or C.sub.1-6 alkyl;
m is zero, 1, 2, or 3;
R.sup.13 R.sup.14 R.sup.15 and R.sup.16 each independently are hydrogen,
C.sub.1-6 alkyl, aryl or arylcarbonyl; or
R.sup.15 and R.sup.16 taken together may form a bivalent radical C.sub.4-5
alkanediyl;
R.sup.17 is hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl;
halomethylcarbonyl;
C.sub.1-6 alkyloxycarbonyl; aryl; di(aryl)methyl; C.sub.1-6 alkyl
substituted with hydroxy, C.sub.1-6 alkyloxy, carboxyl, C.sub.1-6
alkylcarbonyloxy, C.sub.1-6 alkyloxycarbonyl or aryl;
each R.sup.3 independently is halo, cyano, hydroxy, halomethyl,
halomethoxy, carboxyl, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino,
C.sub.1-6 alkylcarbonylamino, aminosulfonyl, mono- or di(C.sub.1-6
alkyl)aminosulfonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6
alkylcarbonyl, C.sub.1-6 -alkyloxycarbonyl;
each R.sup.4 independently is halo, cyano, hydroxy, halomethyl,
halomethoxy, carboxyl, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino,
C.sub.1-6 alkylcarbonylamino, aminosulfonyl, mono- or di(C.sub.1-6
alkyl)aminosulfonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkyloxycarbonyl;
each R.sup.5 independently is C.sub.1-6 alkyl, cyano or halomethyl;
X is CR.sup.6 R.sup.7, NR.sup.8, O, S, S(.dbd.O) or S(.dbd.O).sub.2 ;
wherein
R.sup.6 and R.sup.7 each independently are hydrogen, hydroxy, C.sub.1-6
alkyl, halomethyl, C.sub.1-6 alkyloxy or R.sup.6 and R.sup.7 taken
together may form methylene; mono- or di(cyano)methylene; a bivalent
radical of formula --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --,
--(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --O--(CH.sub.2).sub.2 --O--,
--O--(CH.sub.2).sub.3 --O--; or, together with the carbon atom to which
they are attached, a carbonyl;
R.sup.8 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl,
arylcarbonyl, arylC.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylsulfonyl,
arylsulfonyl or arylC.sub.1-6 alkylsulfonyl;
aryl is phenyl; or phenyl substituted with 1, 2 or 3 substituents selected
from halo, hydroxy, C.sub.1-6 alkyl and halomethyl;
provided that the compound is other than
(.+-.)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:
6,7]-cyclohepta[1,2-b]furan-2-methanamine oxalic acid.
In the foregoing definitions C.sub.1-6 alkyl defines straight and branch
chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms
such as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl,
1,1-dimethylethyl, pentyl, hexyl; C.sub.4-5 alkanediyl defines bivalent
straight and branch chained saturated hydrocarbon radicals having from 4
to 5 carbon atoms such as, for example, 1,4-butanediyl, 1,5-pentanediyl;
halo is generic to fluoro, chloro, bromo and iodo. The term
monocyanomethylene stands for a radical of formula .dbd.CHCN, and
dicyanomethylene for a radical of formula .dbd.C(CN).sub.2. The term
halomethyl is meant to include mono-, di-, and trihalomethyl. Examples of
halomethyl are fluoromethyl, difluoromethyl and particularly
trifluoromethyl. In case R.sup.6 and R.sup.7 taken together form a
bivalent radical of formula --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --,
--(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --O--(CH.sub.2).sub.2 --O--
or --O--(CH.sub.2).sub.3 --O--, the compounds of formula (I) are spiro
compounds.
The pharmaceutically acceptable addition salts as mentioned hereinabove are
meant to comprise the therapeutically active non-toxic base and acid
addition salt forms which the compounds of formula (I) are able to form.
The acid addition salt form of a compound of formula (I) that occurs in
its free form as a base can be obtained by treating the free base form of
the compound of formula (I) with an appropriate acid such as an inorganic
acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic,
sulfuric, nitric, phosphoric and the like acids; or an organic acid, such
as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic,
oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,
methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,
cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The compounds of formula (I) containing acidic protons may be converted
into their therapeutically active non-toxic base, i.e. metal or amine,
addition salt forms by treatment with appropriate organic and inorganic
bases. Appropriate base salt forms comprise, for example, the ammonium
salts, the alkali and earth alkaline metal salts, e.g. the lithium,
sodium, potassium, magnesium, calcium salts and the like, salts with
organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine
salts, and salts with amino acids such as, for example, arginine, lysine
and the like. Conversely said salt forms can be converted into the free
forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates
which the compounds of formula (I) as well as the salts thereof, are able
to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise
those compounds of formula (I) wherein one or several nitrogen atoms are
oxidized to the so-called N-oxide, particularly those N-oxides wherein the
nitrogen bearing the R.sup.1 and R.sup.2 substituents is N-oxidized.
The term "stereochemically isomeric forms" as used hereinbefore and
hereinafter defines all the possible isomeric forms in which the compounds
of formula (I) may occur. Unless otherwise mentioned or indicated, the
chemical designation of compounds denotes the mixture, and in particular
the racemic mixture, of all possible stereochemically isomeric forms, said
mixtures containing all diastereomers and enantiomers of the basic
molecular structure. Stereochemically isomeric forms of the compounds of
formula (I) and mixtures of such forms are intended to be encompassed by
formula (I).
The numbering of the tetracyclic ring-system present in the compounds of
formula (I), as defined by Chemical Abstracts nomenclature is shown in
formula (I').
##STR4##
The compounds of formula (I) have at least three asymmetric centers, namely
carbon atom 2, carbon atom 3a and carbon atom 12b. Said asymmetric centers
and any other asymmetric center which may be present, are indicated by the
descriptors R and S.
When a monocyanomethylene moiety is present in the compounds of formula
(I), said moiety may have the E- or Z-configuration.
The substituents on carbon atoms 3a and 12b, ie. hydrogen or R.sup.5, may
have a cis or trans configuration. In determining said cis or trans
configuration, carbon atoms 3b and 12a are not considered as relevant
substituents as they both are part of the same ring system. When
establishing the configuration of carbon atoms 3a and 12b, the substituent
on carbon atom 3a and the substituent on carbon atom 12b are considered.
They may be on the same side of the mean plane determined by the
tetrahydrofuranyl ring, then the configuration is designated cis, if not,
the configuration is designated trans. Preferably, the substituents on
carbon atoms 3a and 12b are both hydrogen and are each on a different side
of the mean plane determined by the tetrahydrofuranyl ring, i.e. they have
the trans configuration.
Whenever used hereinafter, the term "compounds of formula (I)" is meant to
also include the pharmaceutically acceptable addition salts, the
stereoisomeric forms, and also the N-oxide forms.
A particular group of compounds comprises those compounds of formula (I)
wherein R.sup.13, R.sup.14, R.sup.15 and R.sup.16 each independently are
hydrogen or C.sub.1-6 alkyl.
Of particular interest are those compounds of formula (I) that are other
than
3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:
6,7]-cyclohepta[1,2-b]furan-2-methanamine.
Interesting compounds are those compounds of formula (I) wherein R.sup.1
and R.sup.2 are both C.sub.1-6 alkyl.
Other interesting compounds are those compounds of formula (I) wherein
R.sup.1 and R.sup.2 are taken together with the nitrogen atom to which
they are attached and form a morpholinyl ring; a radical of formula (c),
in particular, a radical of formula (c) wherein m is 2, R.sup.13 is
hydrogen and R.sup.14 is aryl or arylcarbonyl; or a radical of formula
(e), in particular a radical of formula (e) wherein R.sup.17 is aryl,
C.sub.1-6 alkyl or hydroxyC.sub.1-6 alkyl.
Still other interesting compounds are those compounds of formula (I)
wherein X is CR.sup.6 R.sup.7 or O.
Particular compounds are those compounds of formula (I) wherein R.sup.1 and
R.sup.2 are both methyl and n is 1.
Further particular compounds are those compounds of formula (I) wherein p
is 1 and R.sup.3 is halo, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy, in
particular halo.
Other particular compounds are those compounds of formula (I) wherein q is
1 and R.sup.4 is halo, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy, in
particular halo.
Still other particular compounds are those compounds of formula (I) wherein
p, q and r are zero.
Preferred compounds are those particular compounds wherein r is zero and
the hydrogen atoms on carbon atoms 3a and 12b have a trans configuration.
Most preferred are
3,3a,8,12b-tetrahydro-N,N-dimethyl-2H-dibenzo[3,4:
6,7]cyclohepta[1,2-b]furan-2-methanamine; the stereochemically isomeric
forms and the pharmaceutically acceptable addition salts thereof, and the
N-oxide forms thereof, more in particular, those isomeric forms wherein
the hydrogen atoms on carbon atoms 3a and 12b have a trans configuration.
The compounds of formula (I) can generally be prepared by N-alkylating an
intermediate of formula (II) with an intermediate of formula (III) wherein
W is a suitable leaving group such as halo. In the intermediates (II) and
(III), R.sup.1 to R.sup.5, n, p, q, r and X are as defined in the
compounds of formula (I). Said N-alkylation can conveniently be carried
out in a reaction-inert solvent such as, for example, methanol,
methylisobutyl ketone, N,N-dimethylformamide or dimethylsulfoxide, and
optionally in the presence of a suitable base. Stirring and elevated
temperatures, for instance reflux temperature, may enhance the rate of the
reaction. Alternatively, said N-alkylation may also be performed using the
procedure described by Monkovic et al. (J. Med. Chem. (1973), 16(4), p.
403-407) which involves the use of a pressurised reaction vessel.
##STR5##
The compounds of formula (I) may also be converted into each other
following art-known transformation reactions. For instance,
a) a compound of formula (I), wherein R.sup.1 and R.sup.2 taken together
with the nitrogen atom to which they are attached form a radical of
formula (b), may be converted into the corresponding primary amine by
treatment with hydrazine or aqueous alkali;
b) a compound of formula (I), wherein R.sup.1 or R.sup.2 is
trifluoromethylcarbonyl, may be converted into the corresponding primary
or secondary amine by hydrolysis with aqueous alkali;
c) a compound of formula (I), wherein R.sup.1 or R.sup.2 is C.sub.1-6 alkyl
substituted with C.sub.1-6 alkylcarbonyloxy may be hydrolyzed into a
compound of formula (I) wherein R.sup.1 or R.sup.2 is C.sub.1-6 alkyl
substituted with hydroxy;
d) a compound of formula (I), wherein R.sup.1 and R.sup.2 are both hydrogen
may be mono- or di-N-alkylated to the corresponding amine form;
e) a compound of formula (I), wherein R.sup.1 and R.sup.2 are both hydrogen
may be N-acylated to the corresponding amide;
f) a compound of formula (I), containing a C.sub.1-6 alkyloxycarbonyl group
may be hydrolyzed to the corresponding carboxylic acid.
In addition, the compounds of formula (I) wherein X is other than S may be
converted to the corresponding N-oxide forms following art-known
procedures for converting a trivalent nitrogen into its N-oxide form. Said
N-oxidation reaction may generally be carried out by reacting the starting
material of formula (I) with an appropriate organic or inorganic peroxide.
Appropriate inorganic peroxides comprise, for example, hydrogen peroxide,
alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide,
potassium peroxide; appropriate organic peroxides may comprise peroxy
acids such as, for example, benzenecarboperoxoic acid or halo substituted
benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,
peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.
tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower
alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones,
e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and
mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be
obtained by the application of art-known procedures. Diastereomers may be
separated by physical methods such as selective crystallization and
chromatographic techniques, e.g. counter-current distribution, liquid
chromatography and the like.
The compounds of formula (I) as prepared in the hereinabove described
processes are generally racemic mixtures of enantiomers which can be
separated from one another following art-known resolution procedures. The
racemic compounds of formula (I) which are sufficiently basic or acidic
may be converted into the corresponding diastereomeric salt forms by
reaction with a suitable chiral acid respectively with a suitable chiral
base. Said diastereomeric salt forms are subsequently separated, for
example, by selective or fractional crystallization and the enantiomers
are liberated therefrom by alkali or acid. An alternative manner of
separating the enantiomeric forms of the compounds of formula (I) involves
liquid chromatography using a chiral stationary phase. Said pure
stereochemically isomeric forms may also be derived from the corresponding
pure stereochemically isomeric forms of the appropriate starting
materials, provided that the reaction occurs stereospecifically.
Preferably if a specific stereoisomer is desired, said compound will be
synthesized by stereospecific methods of preparation. These methods will
advantageously employ enantiomerically pure starting materials.
The intermediates mentioned hereinabove are either commercially available
or may be made following art-known procedures. For instance, intermediates
of formula (III) may be prepared according to the procedure described by
Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407).
Alternatively, intermediates of formula (III) wherein n is 1 and r is 0,
said intermediates being represented by formula (III-a), can also be
prepared by reacting an epoxide derivative of formula (IV) with a Grignard
reagent of formula (V) wherein X suitably is halo, thus forming an
intermediate of formula (VI) which may subsequently be cyclized according
to art-known methods such as the one described in Monkovic et al.
##STR6##
Epoxides of formula (IV) can be prepared using art-known procedures such as
peroxidating an intermediate of formula (VII) with a suitable peroxide
such as m-chloroperbenzoic acid.
##STR7##
The compounds of the present invention show affinity for 5-HT.sub.2
receptors, particularly for 5-HT.sub.2A and 5-HT.sub.2C receptors
(nomenclature as described by D. Hoyer in "Serotonin (5-HT) in neurologic
and psychiatric disorders" edited by M. D. Ferrari and published in 1994
by the Boerhaave Commission of the University of Leiden). The serotonin
antagonistic properties of the present compounds may be demonstrated by
their inhibitory effect in the "5-hydroxytryptophan Test on Rats" which is
described in Drug Dev. Res., 13, 237-244 (1988). Furthermore, the
compounds of the present invention show interesting pharmacological
activity in the "mCPP Test on Rats" which is described hereinafter, and in
the "Combined Apomorphine, Tryptamine, Norepinephrine (ATN) Test on Rats"
which is described in Arch. Int. Pharmacodyn, 227, 238-253 (1977).
The compounds of the present invention have favourable physicochernical
properties. For instance, they are chemically stable compounds.
In view of these pharmacological and physicochemical properties, the
compounds of formula (I) are useful as therapeutic agents in the treatment
or the prevention of central nervous system disorders like anxiety,
depression and mild depression, bipolar disorders, sleep- and sexual
disorders, psychosis, borderline psychosis, schizophrenia, migraine,
personality disorders or obsessive-compulsive disorders, social phobias or
panic attacks, organic mental disorders, mental disorders in children,
aggression, memory disorders and attitude disorders in older people,
addiction, obesity, bulimia and similar disorders. In particular, the
present compounds may be used as anxiolytics, antipsychotics,
antidepressants, anti-migraine agents and as agents having the potential
to overrule the addictive properties of drugs of abuse.
The compounds of formula (I) may also be used as therapeutic agents in the
treatment of motoric disorders. It may be advantageous to use the present
compounds in combination with classical therapeutic agents for such
disorders.
The compounds of formula (I) may also serve in the treatment or the
prevention of damage to the nervous system caused by trauma, stroke,
neurodegenerative illnesses and the like; cardiovascular disorders like
high blood pressure, thrombosis, stroke, and the like; and
gastrointestinal disorders like dysfunction of the motility of the
gastrointestinal system and the like.
In view of the above uses of the compounds of formula (I), it follows that
the present invention also provides a method of treating warm-blooded
animals suffering from such diseases, said method comprising the systemic
administration of a therapeutic amount of a compound of formula (I)
effective in treating the above described disorders, in particular, in
treating anxiety, psychosis, depression, migraine and addictive properties
of drugs of abuse.
The present invention thus also relates to compounds of formula (I) as
defined hereinabove for use as a medicine, in particular, the compounds of
formula (I) may be used for the manufacture of a medicament for treating
anxiety, psychosis, depression, migraine and addictive properties of drugs
of abuse.
Those of skill in the treatment of such diseases could determine the
effective therapeutic daily amount from the test results presented
hereinafter. An effective therapeutic daily amount would be from about
0.01 mg/kg to about 10 mg/kg body weight, more preferably from about 0.05
mg/kg to about 1 mg/kg body weight.
For ease of administration, the subject compounds may be formulated into
various pharmaceutical forms for administration purposes. To prepare the
pharmaceutical compositions of this invention, a therapeutically effective
amount of the particular compound, optionally in addition salt form, as
the active ingredient is combined in intimate admixture with a
pharmaceutically acceptable carrier, which may take a wide variety of
forms depending on the form of preparation desired for administration.
These pharmaceutical compositions are desirably in unitary dosage form
suitable, preferably, for administration orally, rectally, percutaneously,
or by parenteral injection. For example, in preparing the compositions in
oral dosage form, any of the usual pharmaceutical media may be employed,
such as, for example, water, glycols, oils, alcohols and the like in the
case of oral liquid preparations such as suspensions, syrups, elixirs and
solutions; or solid carriers such as starches, sugars, kaolin, lubricants,
binders, disintegrating agents and the like in the case of powders, pills,
capsules and tablets. Because of their ease in administration, tablets and
capsules represent the most advantageous oral dosage unit form, in which
case solid pharmaceutical carriers are obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at least in
large part, though other ingredients, for example, to aid solubility, may
be included. Injectable solutions, for example, may be prepared in which
the carrier comprises saline solution, glucose solution or a mixture of
saline and glucose solution. Injectable solutions containing compounds of
formula (I) may be formulated in an oil for prolonged action. Appropriate
oils for this purpose are, for example, peanut oil, sesame oil, cottonseed
oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty
acids and mixtures of these and other oils. Injectable suspensions may
also be prepared in which case appropriate liquid carriers, suspending
agents and the like may be employed. In the compositions suitable for
percutaneous administration, the carrier optionally comprises a
penetration enhancing agent and/or a suitable wettable agent, optionally
combined with suitable additives of any nature in minor proportions, which
additives do not cause any significant deleterious effects on the skin.
Said additives may facilitate the administration to the skin and/or may be
helpful for preparing the desired compositions. These compositions may be
administered in various ways, e.g., as a transdermal patch, as a spot-on
or as an ointment. Acid or base addition salts of compounds of formula (I)
due to their increased water solubility over the corresponding base or
acid form, are more suitable in the preparation of aqueous compositions.
In order to enhance the solubility and/or the stability of the compounds of
formula (I) in pharmaceutical compositions, it can be advantageous to
employ .alpha.-, .beta.- or .gamma.-cyclodextrins or their derivatives, in
particular hydroxyalkyl substituted cyclodextrins, e.g.
2-hydroxypropyl-.beta.-cyclodextrin. Also co-solvents such as alcohols may
improve the solubility and/or the stability of the compounds of formula
(I) in pharmaceutical compositions.
It is especially advantageous to formulate the aforementioned
pharmaceutical compositions in dosage unit form for ease of administration
and uniformity of dosage. Dosage unit form as used in the specification
and claims herein refers to physically discrete units suitable as unitary
dosages, each unit containing a predetermined quantity of active
ingredient calculated to produce the desired therapeutic effect, in
association with the required pharmaceutical carrier. Examples of such
dosage unit forms are tablets (including scored or coated tablets),
capsules, pills, powder packets, wafers, injectable solutions or
suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated
multiples thereof.
The following examples are intended to illustrate and not to limit the
scope of the present invention.
EXPERIMENTAL PART
A. PREPARATION OF THE INTERMEDIATE COMPOUNDS
EXAMPLE A.1
a) 3-Bromopropene (0.054 mol) was added dropwise to a mixture of
dibenz[bf]oxepin-10(11H)-one (0.054 mol), prepared according to the
procedure described in C.R. Acad. Sc. Paris, Serie C 1976, 283(15), 683-6,
and potassium tert-butoxide (0.054 mol) in tert-butanol (100 ml), stirred
at room temperature under a N.sub.2 flow. The resulting reaction mixture
was stirred for 2 hours at 80.degree. C., then cooled to room temperature.
The solvent was evaporated. The residue was partitioned between water and
ethylacetate. The organic layer was separated, dried, filtered and the
solvent was evaporated. The residue was purified by HPLC over a LiChroprep
column (eluent:hexane/ethylacetate 98/2). The pure fractions were
collected and the solvent was evaporated, yielding 4.5 g (32%) of
(.+-.)-11-(2-propenyl)dibenz[bf]oxepin-10(11H)-one (interm. 1).
b) Intermediate 1 (0.007 mol) and sodium borohydride (0.0033 mol) were
dissolved in ethanol (40 ml). The reaction solution was stirred for 4
hours at 60.degree. C., then cooled to room temperature. The reaction
mixture was concentrated, then cooled in an ice-water bath. The reaction
was quenched with water and this mixture was extracted with ethylacetate.
The separated organic layer was dried, filtered, and the solvent was
evaporated. The residue was purified by HPLC over a LiChroprep column
(eluent:hexane/ethylacetate 90/10). The pure fractions were collected and
the solvent was evaporated, yielding 0.85 g (50%)
(.+-.)-10,11-dihydro-11-(2-propenyl)dibenz[bf]oxepin-10-ol (interm. 2).
c) Intermediate 2 (0.0047 mol) and pyridine (0.0047 mol) were dissolved in
carbon tetrachloride (40 ml) and the solution was cooled to 0.degree. C.
Bromine (0.0047 mol) was added and the resulting reaction mixture was
stirred for 2 hours at room temperature. The mixture was washed with
water. The organic layer was dried, filtered, and the solvent was
evaporated. The residue was solidified by washing with diisopropylether,
then dried, yielding 0.4 g (25%) of
(.+-.)-2-(bromomethyl)-2,3,3a,12b-tetrahydrodibenzo-[bf]furo[2,3-d]oxepin
(interm. 3).
EXAMPLE A.2
a) 1a,10b-dihydro-6H-dibenzo[3,4:6,7]cyclohept[1,2-b]oxirene (1 g) was
dissolved in 15 ml tetrahydrofuran and cooled to 0.degree. C., under
N.sub.2 atmosphere. Bromo-2-propenyl-magnesium (5,2 ml, 1M in
tetrahydrofuran) was added dropwise to the mixture and the mixture was
stirred at room temperature and then at 60.degree. C. for two hours. The
mixture was cooled to room temperature and quenched with 10% NH.sub.4 Cl
and water, dried and the solvent was evaporated, yielding 0.5 g (48%) of
10,11-dihydro-11-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-10-ol (interm.
4).
b) Pyridinium tribromide (0.63 g) was added portionwise to a solution of
intermediate 4 (0.5 g) in CHCl.sub.3 (15 ml). The mixture was stirred for
one hour at -10.degree. C. and then allowed to warm to room temperature.
The mixture was stirred for another hour and was then washed with water,
extracted, dried and the solvent was evaporated, yielding 0.42 g (65%) of
(.+-.)-2-(bromomethyl)-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:
6,7]cyclohepta[1,2-b]furan (intern. 5).
B. PREPARATION OF THE COMPOUNDS OF FORMULA (I)
The compounds prepared hereinunder all are mixtures of isomeric forms in
which the substituents on carbon atoms 3a and 12b have the trans
configuration, unless otherwise specified.
EXAMPLE B.1
A mixture of intermediate 3 (0.0012 mol) in dimethyl sulfoxide (60 ml) and
chloroform (30 ml) was stirred and cooled to .+-.0.degree. C.
Dimethylamine (gas) was allowed to bubble through the mixture for 15
minutes. The reaction mixture was stirred for 24 hours at 65.degree. C. in
a Parr Pressure vessel. The reaction mixture was cooled to room
temperature and concentrated, washed with water, and extracted with
diethyl ether. The separated organic layer was dried, filtered and the
solvent was evaporated. The residue was purified by HPLC over a LiChroprep
column (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 OH 95/5). The pure fractions
were collected and the solvent was evaporated, yielding 0.14 g (39%) of
(.+-.)-2,3,3a,
12b-tetrahydro-N,N-dimethyldibenzo[bf]furo[2,3-d]oxepin-2-methanamine
(comp. 1).
EXAMPLE B.2
A mixture of intermediate 5 (0.0045 mol) and 1-(2-hydroxyethyl)piperazine
(0.0090 mol) was stirred for 2 hours at 120.degree. C. The mixture was
cooled to room temperature, then taken up into CH.sub.2 Cl.sub.2, filtered
and the filtrate was evaporated. The residue was purified by HPLC over
LiChroprep (eluent: CH.sub.2 Cl.sub.2 /(CH.sub.3 OH, saturated with
NH.sub.3) 96/4). The desired fractions were collected and the solvent was
evaporated. The residue was converted into the hydrochloric acid salt
(1:2). The precipitate was filtered off and dried, yielding 0.73 g (37%)
of
(.+-.)-4-[(3,3a,8,12b-tetrahydro-2H-dibenzo-[3,4:
6,7]cyclohepta[1,2-b]furan-2-yl)methyl]-1-piperazineethanol
dihydrochloride (comp. 3).
EXAMPLE B.3
a) A mixture of intermediate 5 (0.030 mol) and dimethylamine (2 M in
tetrahydrofuran; 150 ml) was diluted with tetrahydrofuran (100 ml) and
stirred overnight at 65.degree. C. in a Parr pressure vessel. The reaction
mixture was cooled to room temperature, and filtered. The filtrate was
evaporated. The residue was purified by HPLC over LiChroprep (eluent:
CH.sub.2 Cl.sub.2 /(CH.sub.3 OH/NH.sub.3 (g)) 98/2). The pure fractions
were collected and the solvent was evaporated. The residue was converted
into the hydrochloric acid salt (1:1). The precipitate was filtered off
and dried, yielding 0.8 g (8%) of
(.+-.)-3,3a,8,12b-tetrahydro-N,N-dimethyl-2H-dibenzo[3,4:
6,7]cyclohepta[1,2-b]furan-2-methanamine hydrochloride (1:1) (comp. 4;
melting point 237.degree. C.). Four pure enantiomers resulted from the
separation of compound 4, i.e. the [2R(2.alpha.,3a.alpha.,12b.beta.)],
[2R,(2.alpha.,3a.beta.,12b.alpha.)], [2S(2.alpha.,3a.alpha.,12b.beta.)]
and [2S(2.alpha.,3a.beta.,12b.alpha.)] isomeric forms.
Table 1 lists compounds of formula (I) which were prepared according to one
of the above examples.
TABLE 1
##STR8##
Co. Ex.
No. No. X R Physical data
1 B.1 CH.sub.2 --N(CH.sub.3).sub.2 (.+-.)
2 B.1 O --N(CH.sub.3).sub.2 (.+-.)
3 B.2 CH.sub.2
##STR9##
(.+-.); HCl (1:1); m.p. 258.degree. C.
4 B.3 CH.sub.2 --N(CH.sub.3).sub.2 (.+-.); HCl (1:1);
mp. 237.degree. C.
4a B.3 CH.sub.2 --N(CH.sub.3).sub.2
[2R(2.alpha.,3a.alpha.,12b.beta.)]
4b B.3 CH.sub.2 --N(CH.sub.3).sub.2
[2R(2.alpha.,3a.beta.,12b.alpha.)]
4c B.3 CH.sub.2 --N(CH.sub.3).sub.2
[2S(2.alpha.,3a.alpha.,12b.beta.)]
4d B.3 CH.sub.2 --N(CH.sub.3).sub.2
[2S(2.alpha.,3a.beta.,12b.alpha.)]
5 B.2 CH.sub.2
##STR10##
(.+-.); m.p. 276.degree. C.; H.sub.2 O (1:2).HCl (1:1)
6 B.2 CH.sub.2
##STR11##
(.+-.); HCl (1:1)
7 B.2 CH.sub.2
##STR12##
(.+-.); m.p. 208.degree. C.; HBr (1:1)
8 B.2 CH.sub.2
##STR13##
(.+-.); m.p. 253.degree. C.; H.sub.2 O (1:1).HCl (1:1)
9 B.2 CH.sub.2
##STR14##
(.+-.); m.p. 284.degree. C.; HCl (1:1)
C. PHARMACOLOGICAL EXAMPLE
Example C.1: "mCPP Test on Rats"
Rats were treated with the test compound at a dose varying between 0.0025
mg/kg and 40 mg/kg body weight at a pre-test time T of 1 hour, and with 1
mg/kg mCPP (metachlorophenylpiperazine), injected intravenously, 15
minutes prior to the test. After pretest time T elapsed, treated rats were
submitted to the "Open Field Test on Rats" as described in Drug Dev. Res.
18, 119-144 (1989), but using an infra-red light source instead of a
Kleverlux.RTM. (12V/20 W) light source. A dose at which 40% of the tested
rats showed suppression of the mCPP induced effects, i.e. mCPP-antagonism,
was defined as an active dose. Compounds number 1, 2, 4 and 9 were active
at a test dose of 2.5 mg/kg or less.
Example C.2: In Vitro Binding Affinity for 5-HT.sub.2A and 5-HT.sub.2C
Receptors
The interaction of the compounds of formula (I) with 5-HT.sub.2A and
5-HT.sub.2C receptors was assessed in in vitro radioligand binding
experiments.
In general, a low concentration of a radioligand with a high binding
affinity for the receptor is incubated with a sample of a tissue
preparation enriched in a particular receptor (1 to 5 mg tissue) in a
buffered medium (0.2 to 5 ml). During the incubation, the radioligands
bind to the receptor. When equilibrium of binding is reached, the receptor
bound radioactivity is separated from the non-bound radioactivity, and the
receptor bound activity is counted. The interaction of the test compounds
with the receptors is assessed in competition binding experiments. Various
concentrations of the test compound are added to the incubation mixture
containing the tissue preparation and the radioligand. Binding of the
radioligand will be inhibited by the test compound in proportion to its
binding affinity and its concentration.
The radioligand used for 5-HT.sub.2A binding affinity is .sup.3
H-ketanserin and the tissue used is the frontal cortex of the rat. At a
test concentration of 10.sup.-7 M, the compounds with number 3, 4, 5, 8
and 9 produced an inhibition of the 5-HT.sub.2A receptor of more than 40%,
and the other compounds produced an inhibition of less than 40%.
The radioligand used for 5-HT.sub.2C binding affinity is .sup.3
H-mesulergine and the tissue used is the choroid plexus of the pig. At a
test concentration of 10.sup.-7 M, the compounds with number 1, 3, 4, 5,
6, 7, 8 and 9 produced an inhibition of the 5-HT.sub.2C receptor of more
than 40%, and compound number 2 produced an inhibition of less than 40%.
D. COMPOSITION EXAMPLES
"Active ingredient" (A.I.) as used throughout these examples relates to a
compound of formula (I), a pharmaceutically acceptable acid addition salt,
a stereochemically isomeric form thereof or a N-oxide form thereof.
Example D.1: ORAL SOLUTION
Methyl 4-hydroxybenzoate (9 g) and propyl 4-hydroxybenzoate (1 g) were
dissolved in boiling purified water (4 l). In 3 l of this solution were
dissolved first 2,3-dihydroxybutanedioic acid (10 g) and thereafter A.I
(20 g). The latter solution was combined with the remaining part of the
former solution and 1,2,3-propanetriol (12 l) and sorbitol 70% solution (3
l) were added thereto. Sodium saccharin (40 g) were dissolved in water
(500 ml) and raspberry (2 ml) and gooseberry essence (2 ml) were added.
The latter solution was combined with the former, water was added q.s. to
a volume of 20 l providing an oral solution comprising 5 mg of the active
ingredient per teaspoonful (5 ml). The resulting solution was filled in
suitable containers.
Example D.2: FILM-COATED TABLETS
Preparation of Tablet Core
A mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixed
well and thereafter humidified with a solution of sodium dodecyl sulfate
(5 g) and polyvinylpyrrolidone (10 g) in water (200 ml). The wet powder
mixture was sieved, dried and sieved again. Then there was added
microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g).
The whole was mixed well and compressed into tablets, giving 10.000
tablets, each containing 10 mg of the active ingredient.
Coating
To a solution of methyl cellulose (10 g) in denaturated ethanol (75 ml)
there was added a solution of ethyl cellulose (5 g) in dichloromethane
(150 ml). Then there were added dichloromethane (75 ml) and
1,2,3-propanetriol (2.5 ml). Polyethylene glycol (10 g) was molten and
dissolved in dichloromethane (75 ml). The latter solution was added to the
former and then there were added magnesium octadecanoate (2.5 g),
polyvinylpyrrolidone (5 g) and concentrated colour suspension (30 ml) and
the whole was homogenated. The tablet cores were coated with the thus
obtained mixture in a coating apparatus.
Example D.3: INJECTABLE SOLUTION
Methyl 4hydroxybenzoate (1.8 g) and propyl 4-hydroxybenzoate (0.2 g) were
dissolved in boiling water (500 ml) for injection. After cooling to about
50.degree. C. there were added while stirring lactic acid (4 g), propylene
glycol (0.05 g) and A.I. (4 g). The solution was cooled to room
temperature and supplemented with water for injection q.s. ad 1000 ml,
giving a solution comprising 4 mg/ml of A.I. The solution was sterilized
by filtration and filled in sterile containers.
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